This invention relates to novel sulfonamide substituted diphenyl urea compounds, pharmaceutical compositions, processes for their preparation, and use thereof in treating IL-8, GROxcex1, GROxcex2, GROxcex3, NAP-2, and ENA-78 mediated diseases.
Many different names have been applied to Interleukin-8 (IL-8), such as neutrophil attractant/activation protein-1 (NAP-1), monocyte derived neutrophil chemotactic factor (MDNCF), neutrophil activating factor (NAF), and T-cell lymphocyte chemotactic factor. Interleukin-8 is a chemoattractant for neutrophils, basophils, and a subset of T-cells. It is produced by a majority of nucleated cells including macrophages, fibroblasts, endothelial and epithelial cells exposed to TNF, IL-1xcex1, IL-1xcex2 or LPS, and by neutrophils themselves when exposed to LPS or chemotactic factors such as FMLP. M. Baggiolini et al., J. Clin. Invest. 84, 1045 (1989); J. Schroder et al, J. Immunol. 139, 3474 (1987) and J. Immunol. 144, 2223 (1990); Strieter, et al., Science 243, 1467 (1989) and J. Biol. Chem. 264, 10621 (1989); Cassatella et al., J. Immunol. 148, 3216 (1992).
GROxcex1, GROxcex2, GROxcex3 and NAP-2 also belong to the chemokine family. Like IL-8 these chemokines have also been referred to by different names. For instance GROxcex1, xcex2, xcex3 have been referred to as MGSAxcex1, xcex2 and xcex3 respectively (Melanoma Growth Stimulating Activity), see Richmond et al., J. Cell Physiology 129, 375 (1986) and Chang et al., J. Immunol 148,451 (1992). All of the chemokines of the xcex1-family which possess the ELR motif directly preceding the CXC motif bind to the IL-8 B receptor (CXCR2).
IL-8, GROxcex1, GROxcex2, GROxcex3, NAP-2, and ENA-78 stimulate a number of functions in vitro. They have all been shown to have chemoattractant properties for neutrophils, while IL-8 and GROxcex1 have demonstrated T-lymphocytes, and basophilic chemotactic activity. In addition IL-8 can induce histamine release from basophils from both normal and atopic individuals. GRO-xcex1 and IL-8 can in addition, induce lysozomal enzyme release and respiratory burst from neutrophils. IL-8 has also been shown to increase the surface expression of Mac-1 (CD11b/CD18) on neutrophils without de novo protein synthesis. This may contribute to increased adhesion of the neutrophils to vascular endothelial cells. Many known diseases are characterized by massive neutrophil infiltration. As IL-8, GROxcex1, GROxcex2, GROxcex3 and NAP-2 promote the accumulation and activation of neutrophils, these chemokines have been implicated in a wide range of acute and chronic inflammatory disorders including psoriasis and rheumatoid arthritis, Baggiolini et al., FEBS Lett. 307, 97 (1992); Miller et al., Crit. Rev. inmunol. 12, 17 (1992); Oppenheim et al., Annu. Rev. Immunol. 9, 617 (1991); Seitz et al., J. Clin. Invest. 87, 463 (1991); Miller et al., Am. Rev. Respir. Dis. 146, 427 (1992); Donnely et al., Lancet 341, 643 (1993). In addition the ELR chemokines (those containing the amino acids ELR motif just prior to the CXC motif) have also been implicated in angiostasis, Strieter et al., Science 258, 1798 (1992).
In vitro, IL-8, GROxcex1, GROxcex2, GROxcex3 and NAP-2 induce neufrophil shape change, chemotaxis, granule release, and respiratory burst, by binding to and activating receptors of the seven-transmembrane, G-protein-linked family, in particular by binding to IL-8 receptors, most notably the IL-8xcex2 receptor (CXCR2). Thomas et al., J. Biol. Chem. 266, 14839 (1991); and Holmes et al., Science 253, 1278 (1991). The development of non-peptide small molecule antagonists for members of this receptor family has precedent. For a review see R. Freidinger in Progress in Drug Research, Vol. 40, pp. 33-98, Birkhauser Verlag, Basel 1993. Hence, the IL-8 receptor represents a promising target for the development of novel anti-inflammatory agents.
Two high affinity human IL-8 receptors (77% homology) have been characterized: IL-8Rxcex1, which binds only IL-8 with high affinity, and IL-8Rxcex2, which has high affinity for IL-8 as well as for GROxcex1, GROxcex2, GROxcex3 and NAP-2. See Holmes et al., supra; Murphy et al., Science 253, 1280 (1991); Lee et al., J. Biol. Chem. 267, 16283 (1992); LaRosa et al., J. Biol. Chem. 267,25402 (1992); and Gayle et al., J. Biol. Chem. 268, 7283 (1993).
There remains a need for treatment, in this field, for compounds, which are capable of binding to the IL-8 xcex1 or xcex2 receptor. Therefore, conditions associated with an increase in IL-8 production (which is responsible for chemotaxis of neutrophil and T-cells subsets into the inflammatory site) would benefit by compounds, which are inhibitors of IL-8 receptor binding.
This invention provides for a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 a or b receptor and which method comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In particular the chemokine is IL-8.
This invention also relates to a method of inhibiting the binding of IL-8 to its receptors in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I).
The present invention also provides for the novel compounds of Formula (I), and pharmaceutical compositions comprising a compound of Formula (I), and a pharmaceutical carrier or diluent.
Compounds of Formula (I) useful in the present invention are represented by the structure: 
wherein
Rb is independently selected rom the group consisting of hydrogen, NR6R7, OH, ORa, C1-5alkyl, aryl, arylC1-4alkyl, aryl C2-4alkenyl; cycloalkyl, cycloalkyl C1-5 alkyl, heteroaryl, heteroarylC1-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic C1-4alkyl, and a heterocyclic C2-4alkenyl, all of which moieties may be optionally substituted one to three times independently by a substituent selected from the group consisting of halogen, nitro, halosubstituted C1-4 alkyl, C1-4 alkyl, amino, mono or di-C1-4 alkyl substituted amine, ORa, C(O)Ra, NRaC(O)ORa, OC(O)NR6R7, hydroxy, NR9C(O)Ra, S(O)mxe2x80x2Ra, C(O)NR6R7, C(O)OH, C(O)ORa, S(O)2NR6R7, NHS(O)2Ra, or, the two Rb substituents join to form a 3-10 membered ring, optionally substituted and containing, in addition to carbon, independently, 1 to 3 moieties selected from the group consisting of NRa, O, S, SO, or SO2; and wherein the substituent can be optionally unsaturated;
Rais selected from the group consisting of alkyl, aryl, arylC1-4alkyl, heteroaryl, heteroaryl C1-4alkyl, heterocyclic, COOR13, and a heterocyclic C1-4alkyl moiety, all of which moieties may be optionally substituted;
m is an integer having a value of 1 to 3;
mxe2x80x2 is 0, or an integer having a value of 1 or 2;
q is 0, or an integer having a value of 1 to 10;
t is 0, or an integer having a value of 1 or 2;
s is an integer having a value of 1 to 3;
R1 is independently selected from the froup consisting of hydrogen, halogen, nitro, cyano, C1-10 alkyl, halosubstituted C1-10 alkyl, C2-10 alkenyl, C1-10 alkoxy, halosubstituted C1-10alkoxy, azide, S(O)tR4, (CR8R8)q S(O)tR4, hydroxy, hydroxy substituted C1-4alkyl, aryl, aryl C1-4 alkyl, aryl C2-10 alkenyl, aryloxy, aryl C1-4 alkyloxy, heteroaryl, heteroarylalkyl, heteroaryl C2-10 alkenyl, heteroaryl C1-4 alkyloxy, heterocyclic, heterocyclic C1-4alkyl, heterocyclic C1-4alkyloxy, heterocyclic C2-10 alkenyl, (CR8R8)q NR4R5(CR8R8)q C(O)NR4R5, C2-10 alkenyl C(O)NR4R5, (CR8R8)qC(O)NR4R10, S(O)3R8, (CR8R8)qC(O)R11, C2-10 alkenyl C(O)R11, C2-10 alkenyl C(O)OR11, (CR8R8)qC(O)OR11, (CR8R8)qOC(O)R11, (CR8R8)qNR4C(O)R11, (CR8R8)qC(NR4)NR4R5, (CR8R8)qNR4C(NR5)R11, (CR8R8)qNHS(O)2R13, and (CR8R8)qS(O)2NR4R5; or two R1 moieties together may form Oxe2x80x94(CH2)sO or a 5 to 6 membered saturated or unsaturated ring, and wherein the alkyl, aryl, arylalkyl, heteroaryl, heterocyclic moieties may be optionally substituted;
R4 and R5 are independently selected from the group consisting of hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1-4alkyl, heterocyclic, and heterocyclic C1-4 alkyl; or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O, N and S;
R6 and R7 are independently selected from the group consisting of hydrogen, C1-4 alkyl, heteroaryl, aryl, alkyl aryl, and alkyl C1-4 heteroalkyl; or R6 and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom is selected from oxygen, nitrogen and sulfur; wherein the ring may be optionally substituted;
Y is selected from the group conisting of CR14C15, NR14, O, CO, and S(O)t 
R8 is hydrogen or C1-4 alkyl;
R9 is C1-4 alkyl;
R10 is C1-10 alkyl C(O)2R8;
R11 is selected from the group consisting of hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC1-4alkyl, optionally substituted heterocyclic, and optionally substituted heterocyclicC1-4alkyl; and
R12 is selected from the group consisting of hydrogen C1-4 alkyl, aryl, aryl C1-4alkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclic, and heterocyclicC1-4alkyl;
R13 is selected from the group consisting of C1-4 alkyl, aryl, aryl C1-4alkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclic, and heterocyclicC1-4alkyl;
R14 and R15 are, independently, selected from the group consisting of hydrogen, optionally substituted C1-4 alkyl group, ORa, and NR4R5; or R14 and R15 together with the atom(s) to which they are attached may form a 4 to 7 member ring which may optionally contain an additional heteroatom which heteroatom is selected from the group consisting of oxygen, nitrogen and sulfur; wherein the ring maybe optionally substituted;
or a pharmaceutically acceptable salt thereof.
The compounds of Formula (I), may also be used in association with the veterinary treatment of mammals, other than humans, in need of inhibition of IL-8 or other chemokines which bind to the IL-8 xcex1 and xcex2 receptors. Chemokine mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted herein in the Methods of Treatment section.
Suitably, Rb is independently hydrogen, NR6R7, OH, ORa, C1-4alkyl, aryl, arylC1-4alkyl, aryl C2-4alkenyl, heteroaryl, heteroarylC1-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic C1-4alkyl, or a heterocyclic C2-4alkenyl moiety, all of which moieties may be optionally substituted one to three times independently by halogen, nitro, halosubstituted C1-4 alkyl, C1-4 alkyl, amino, mono or di-C1-4 alkyl substituted amine, cycloalkyl, cycloalkyl C1-5 alkyl, ORa, C(O)Ra, NRaC(O)ORa, OC(O)NR6R7, aryloxy, aryl C1-4 oxy, hydroxy, C1-4 alkoxy, NR9C(O)Ra, S(O)mxe2x80x2Ra, C(O)NR6R7, C(O)OH, C(O)ORa, S(O)2NR6R7, NHS(O)2Ra. Alternatively, the two Rb substituents can join to form a 3-10 membered ring, optionally substituted and containing, in addition to carbon, independently, 1 to 3 NR9, O, S, SO, or SO2 moities which can be optionally substituted.
Suitably, Rais an alkyl, aryl, arylC1-4alkyl, heteroaryl, heteroaryl C1-4alkyl, heterocyclic, or a heterocyclic C1-4alky moiety, all of which moieties may be optionally substituted.
Suitably, R1 is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted C1-10 alkyl, such as CF3, C1-10 alkyl, such as methyl, ethyl, isopropyl, or n-propyl, C2-10 alkenyl, C1-10 alkoxy, such as methoxy, or ethoxy; halosubstituted C1-10 alkoxy, such as trifluoromethoxy, azide, (CR8R8)qS(O)tR4, wherein t is 0, 1 or 2, hydroxy, hydroxy C1-4alkyl, such as methanol or ethanol, aryl, such as phenyl or naphthyl, aryl C1-4 alkyl, such as benzyl, aryloxy, such as phenoxy, aryl C1-4 alkyloxy, such as benzyloxy; heteroaryl, heteroarylalkyl, heteroaryl C1-4 alkyloxy; aryl C2-10 alkenyl, heteroaryl C2-10 alkenyl, heterocyclic C2-10 alkenyl, (CR8R8)qNR4R5, C2-10 alkenyl C(O)NR4R5, (CR8R8)qC(O)NR4R5, (CR8R8)qC(O)NR4R10, S(O)3H, S(O)3R8, (CR8R8)qC(O)R11, C2-10 alkenyl C(O)R11, C2-10 alkenyl C(O)OR11, (CR8R8)qC(O)R11, (CR8R8)qC(O)OR11(CR8R8)q OC(O)R11, (CR8R8)qNR4C(O)R11, (CR8R8)qC(NR4)NR4R5, (CR8R8)qNR4C(NR5)R11, (CR8R8)qNHS(O)2R13, (CR8R8)qS(O)2NR4R5. All of the aryl, heteroaryl, and heterocyclic-containing moieties may be optionally substituted as defined herein below.
For use herein the term xe2x80x9cthe aryl, heteroaryl, and heterocyclic containing moietiesxe2x80x9d refers to both the ring and the alkyl, or if included, the alkenyl rings, such as aryl, arylalkyl, and aryl alkenyl rings. The term xe2x80x9cmoietiesxe2x80x9d and xe2x80x9cringsxe2x80x9d may be interchangeably used throughout.
Suitably, R4 and R5 are independently hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl, optionally substituted aryl C1-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C1-4alkyl, heterocyclic, heterocyclicC1-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O, N and S.
Suitably R6 and R7 are hydrogen, or a C1-4 alkyl, heteroaryl, alkyl C1-4 heteroalkyl or R6 and R7 together with the nitrogen to which they are attached form a 5 to 7-member ring which ring may optionally contain an additional heteroatom that is selected from oxygen, nitrogen or sulfur, and which ring may be optionally substituted;
Suitably, R8 is independently hydrogen or C1-4 alkyl.
Suitably, R9 is hydrogen or a C1-4 alkyl;
Suitably, q is 0 or an integer having a value of 1 to 10.
Suitably, R10 is C1-10 alkyl C(O)2R8, such as CH2C(O)2H or CH2C(O)2CH3.
Suitably, R11 is hydrogen, C1-4 alkyl, aryl, aryl C1-4 alkyl, heteroaryl, heteroaryl C1-4alkyl, heterocyclic, or heterocyclic C1-4alkyl.
Suitably, R12 is hydrogen, C1-10 alkyl, aryl or arylalkyl.
Suitably, R13 is C1-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclic, or heterocyclicC1-4alkyl, wherein all of the aryl, heteroaryl and heterocyclic containing moieties may all be optionally substituted.
R14 and R15 are suitably hydrogen, optionally substituted C1-4 alkyl group, ORa, NR4R5 or R14 and R15 together with the atom (s) to which they are attached may form a 4 to 7 member ring which may optionally contain an additional heteroatom which is selected from oxygen, nitrogen or sulfur; this ring maybe optionally substituted.
Suitably, Y is CR14R15, NR14, O
Suitably, Rais an alkyl, aryl C1-4 alkyl, heteroaryl, heteroaryl-C1-4alkyl, heterocyclic, or a heterocyclicC1-4 alkyl, wherein all of these moieties may all be optionally substituted.
As used herein, xe2x80x9coptionally substitutedxe2x80x9d unless specifically defined shall mean such groups as halogen, such as fluorine, chlorine, bromine or iodine, hydroxy; hydroxy substituted C1-10alkyl, C1-10 alkoxy, such as methoxy or ethoxy, S(O)mxe2x80x2C1-10 alkyl, wherein mxe2x80x2 is 0, 1 or 2, such as methyl thio, methyl sulfinyl or methyl sulfonyl; amino, mono and di-substituted amino, such as in the NR8R12 group, NHC(O)R13, C(O)NR8R12, C(O)OH, S(O)2NR8R12, NHS(O)2R13, C1-10 alkyl, such as methyl, ethyl, propyl, isopropyl, or t-butyl, halosubstituted C1-10 alkyl, such CF3, an optionally substituted aryl, such as phenyl, or an optionally substituted arylalkyl, such as benzyl or phenethyl, optionally substituted heterocylic, optionally substituted heterocyclicalkyl, optionally substituted heteroaryl, optionally substituted heteroaryl alkyl, wherein these aryl, heteroaryl, or heterocyclic moieties may be substituted one to two times by halogen; hydroxy; hydroxy substituted alkyl, C1-10 alkoxy; S(O)mxe2x80x2C1-10 alkyl; amino, mono and di-substituted alkyl amino, such as in the NR6R7 group; C1-10 alkyl, or halosubstituted C1-10 alky, such as CF3.
Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid. In addition, pharmaceutically acceptable salts of compounds of Formula (I) may also be formed with a pharmaceutically acceptable cation. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations.
The following terms, as used herein, refer to:
xe2x80x9chaloxe2x80x9dxe2x80x94all halogens, that is chloro, fluoro, bromo and iodo.
xe2x80x9cC1-10alkylxe2x80x9d or xe2x80x9calkylxe2x80x9dxe2x80x94both straight and branched chain moieties of 1 to 10 carbon atoms, unless the chain length is otherwise limited, including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl and the like.
xe2x80x9ccycloalkylxe2x80x9d is used herein to mean cyclic moiety, preferably of 3 to 8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like.
xe2x80x9calkenylxe2x80x9d is used herein at all occurrences to mean straight or branched chain moiety of 2-10 carbon atoms, unless the chain length is limited thereto, including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.
xe2x80x9carylxe2x80x9dxe2x80x94phenyl and naphthyl;
xe2x80x9cheteroarylxe2x80x9d (on its own or in any combination, such as xe2x80x9cheteroaryloxyxe2x80x9d, or xe2x80x9cheteroaryl alkylxe2x80x9d)xe2x80x94a 5-10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S, such as, but not limited, to pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, tetrazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole.
xe2x80x9cheterocyclicxe2x80x9d (on its own or in any combination, such as xe2x80x9cheterocyclicalkylxe2x80x9d)xe2x80x94a saturated or partially unsaturated 4-10 membered ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O, or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, thiomorpholine, or imidazolidine. Furthermore, sulfur may be optionally oxidized to the sulfone or the sulfoxide.
xe2x80x9carylalkylxe2x80x9d or xe2x80x9cheteroarylalkylxe2x80x9d or xe2x80x9cheterocyclicalkylxe2x80x9d is used herein to mean C1-10 alkyl, as defined above, attached to an aryl, heteroaryl or heterocyclic moiety, as also defined herein, unless otherwise indicated.
xe2x80x9csulfinylxe2x80x9dxe2x80x94the oxide S(O) of the corresponding sulfide, the term xe2x80x9cthioxe2x80x9d refers to the sulfide, and the term xe2x80x9csulfonylxe2x80x9d refers to the fully oxidized S(O)2 moiety.
xe2x80x9cwherein two R1 moieties may together form a 5 or 6 membered saturated or unsaturated ringxe2x80x9d is used herein to mean the formation of an aromatic ring system, such as naphthalene, or is a phenyl moiety having attached a 6 membered partially saturated or unsaturated ring such as a C6 cycloalkenyl, i.e. hexene, or a C5 cycloalkenyl moiety, such as cyclopentene.
Illustrative compounds of Formula (I) include:
N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-Nxe2x80x2-cyclohexylurea;
N-(3-aminosulfonyl-4-chloro-2-hydroxyphenyl)-Nxe2x80x2-(1-adamantyl)urea;
N-(3-arninosulfonyl-4-chloro-2-hydroxyphenyl)-Nxe2x80x2-(tetrahydro-2-pyranyl)urea;
N-[4-chloro-2-hydroxy-3-sulfamylphenyl]-Nxe2x80x2-(3-tetrahydrofuryl)urea;
6-Chloro-2-hydroxy-3-[3-(2-methyl-cyclopropyl)-ureido]-benzenesulfonamide;
N-[4-chloro-2-hydroxy-3-sulfamylphenyl]-Nxe2x80x2-cyclohexylurea;
6-Chloro-2-hydroxy-3-[3-(2,2,3,3-tetrmethyl-cyclopropyl)-ureido]-benzenesulfonarnide;
6-Chloro-2-hydroxy-3-(3-piperidin-4-yl-ureido)-benzenesulfonamide;
N-[4-chloro-2-hydroxy-3-sulfamylphenyl]-Nxe2x80x2-(4-methyl-cyclohexyl) urea;
6-Chloro-2-hydroxy-3-[3-(3-methoxy-cyclohexyl)-ureido]-benzenesulfonamide;
N-[4-chloro-2-hydroxy-3-sulfamylphenyl]-Nxe2x80x2-cyclopentylurea;
N-[4-chloro-2-hydroxy-3-sulfamylphenyl]-Nxe2x80x2-cyclobutylurea;
N-[4-chloro-2-hydroxy-3-sulfamylphenyl]-Nxe2x80x2-cyclopropylurea;
4-[6-Chloro-3-(3-cyclopentyl-ureido)-2-hydroxy-benzenesulfonyl]-piperazine-1-carboxylic acid tert butyl ester;
1-[4-Chloro-2-hydroxy-3-(piperazine-1-sulfonyl)-phenyl]-3-cyclopentyl-urea;
4-[6-Chloro-3-(3-cyclobutyl-ureido)-2-hydroxy-benzenesulfonyl]-piperazine-1-carboxylic acid tert-butyl ester;
3-[3-((1S,2S)-2-Benzyloxy-cyclohexyl)-ureido]-6-chloro-2-hydroxy-benzenesulfonamide; and
6-Chloro-3-(3-cyclobutyl-ureido)-2-hydroxy-N,Nxe2x80x2-dimethyl-benzenesulfonamide.
The compounds of Formulas (I) may be obtained by applying synthetic procedures, some of which are illustrated in the Schemes below. The synthesis provided for in these Schemes is applicable for the producing compounds of Formulas (I), having a variety of different R, Rb, and Y groups which are reacted, employing optional substituents which are suitably protected, to achieve compatibility with the reactions outlined herein. Subsequent deprotection, in those cases, then affords compounds of the nature generally disclosed. Once the urea nucleus has been established, further compounds of these formulas may be prepared by applying standard techniques for functional group interconversion, well known in the art. 
The desired 4-chloro N-(3-sulfonamido-2-hydroxy phenyl)-Nxe2x80x3-cycloaikyl urea can synthesized from the commercially available 2,6-dichloro thiophenol using the procedure elaborated above in Scheme 1. The thiol can be oxidized to the corresponding sulfonyl halide using a halogenating agent, such as NCS, NBS, Cl2 or Br2, in the presence of a protic solvent, such as water, acetic acid, or an alcohol or combination. The yield may be increased if a buffering agent, such as sodium or potassium acetate is included in the reaction mixture, and the reaction is conducted at or below room temperature. The corresponding sulfonyl halide can then be condensed with an amine in presence of a base such as pyridine, triethyl amine, potassium carbonate or sodium hydride to form the analogous sulfonamide 2-scheme 1. The dichlorosulfonamide 2-scheme 1 can be nitrated using strong nitrating conditions such as nitric acid in sulfuric acid to form the aromatic nitro compound 3-scheme 1. The chlorine ortho to the nitro group can be selectively hydrolyzed using acetate salt such as sodium acetate in the presence of a crown ether, such as 18-crown-6, to form the acetate 4-scheme 1. The acetate group can be hydrolyzed under acidic conditions in an alcohol solvent such as methanol or ethanol with a catalytic amount of acid to form the phenol 5-scheme 1. The nitro can be reduced by conditions well known in the art such as hydrogen and palladium on carbon, tin chloride in methanol, zinc in acetic acid or thiol to form the corresponding aniline 5-scheme 1. The aniline can then be coupled with a commercially available isocyanate or thioisocyanate to form the desired urea or thio urea. Alternatively the desired isocyanates can be made by condensing the amine with triphosgene in the presence of base (such as potassium carbonate) or by reacting the carboxylic acid with diphenyl phosphoryl azide in the presence of a base (such as triethyl amine). 
If the sulfonamide 1-scheme 2 (3-scheme 1) is unfunctionalized Rxe2x80x2=Rxe2x80x3=H then it can be functionalized as required herein, by alkylation. The sulfonamide is deprotonated using a base such as sodium hydride and then alkylated using an alkyl halide such as benzyl bromide or methyl iodide form 2-scheme 2. The sulfonamide can then be alkylated a second time using sodium hydride and another alkyl halide to form 3-scheme 2. This compound can then be converted to the desired urea using the process elaborated in scheme 1.
An alternative route to 5-scheme 3 (3-scheme 1) is outlined above, in scheme 3 wherein the commercially available 2,6-dichloro thiol can be oxidized to the sulfonyl halide using a halogenating agent such as NCS, NBS, chlorine or bromine in the presence of a protic solvent such as alcohol, acetic acid or water. The sulfonyl halide can be hydrolyzed by using a metal hydroxide such as sodium or potassium hydroxide to form the corresponding sulfonic acid salt. The sulfonic acid salt can then be nitrated under nitration conditions such as nitric acid in a solvent of strong acid such as sulfuric acid to form the nitro phenyl sulfonic acid 3-scheme 3. The sulfonic acid 3-scheme 3 can be converted to the sulfonamide 5-scheme 3 using a three step procedure involving the formation of the metal salt using a base such as sodium hydroxide, sodium hydride or sodium carbonate to form 4-scheme 3. The sulfonic acid salt is then converted to the sulfonyl chloride using PCl5 with POCl3 as a solvent. The sulfonyl chloride can then be converted to the corresponding sulfonamide using the desired amine HNRxe2x80x2Rxe2x80x3 in triethyl amine at temperatures ranging from xe2x88x9278xc2x0 C. to 60xc2x0 C. to form the corresponding sulfonamide 5-scheme 3 (3-scheme 1). The sulfonamide 5-scheme 3 can be further elaborated by the methods contained in scheme 1. This method is not limited to the 2,6-dichloro thiol it can also be applied to the 2,6-diflouro thiol, 2,6-dibromo thiol and the 2,6-diiodo thiol. The halogens in these compounds can be converted to the corresponding cyano, amino, thiol, or alkoxy compounds by nucleophilic displacement reactions using nucleophiles such as alkyl thiolates, alkoxides, amine and cyanides. The halogens can also be further functionalized by palladium coupling and carbonylation reactions, well known in the art, to form the corresponding amido, carbonyl, alkenyl, alkyl, phenyl and heterocyclic substituted products as required by Formula (I).